RESEARCH PROPOSAL: Breast cancer rivals lung cancer as one of the leading causes of morbidity and mortality in U.S. women, accounting for approximately 25% of their cancer deaths. Significant progress has been made in understanding the genetics of breast cancer including the recent identification of a critical tumor suppressor gene, BRCA1. Other genes, including TP53 and MTS1, have demonstrated involvement in breast carcinogenesis. In general, cancer arises from cells that escape normal growth regulation enabling them to proliferate rapidly, invade locally and metastasize to distant sites. Genetic study of colorectal cancer has shown that tumorigenesis is the result of a multistep molecular process involving both the activation of protooncogenes and inactivation of tumor suppressor genes. Both gene amplification and loss of heterozygosity (LOH) studies support the hypothesis that alterations in multiple interacting growth-regulatory genes are critical in breast carcinogenesis. Characterization of all these alterations is necessary to understand their interrelated roles in breast cancer and to ultimately facilitate improved medical management of breast cancer for all women. The goal of this research is to isolate a putative breast cancer gene which has been recently localized to chromosome 17q25 (distal to BRCA1) by LOH and cytogenetic studies. The specific aims are to: 1) Define the smallest region of LOH on 17q25 by analysis of matched tumor and normal tissue with existing and newly developed highly polymorphic microsatellite markers 2) Analyze non-random 17q25 cytogenetic translocation breakpoints in breast carcinomas 3) Construct a YAC/P1 contig spanning the smallest region of LOH 4) Isolate expressed DNA sequences from this interval and 5) Elucidate this gene's role in breast cancer.